PPARs are known to be a family of nuclear receptors, and three sub-types thereof (α, γ, δ) have already been identified (Non-Patent Documents 1 to 5). Among the three sub-types, PPARα is expressed primarily in the liver and is known to be activated by a plasticizer or a fibrate-type drug such as Wy 14643 or a commercially available pharmaceutical; e.g., clofibrate, fenofibrate, bezafibrate, or gemfibrozil (Non-Patent Documents 6 and 7).
In mammals, activation of PPARα is known to promote β oxidation of fatty acids and to lower blood triglyceride level, and in humans, blood lipid levels such as low-density lipoprotein (LDL) cholesterol level and very low-density lipoprotein (VLDL) cholesterol level are known to decrease. Thus, a PPARα-activating agent is considered a useful drug for preventing and/or treating diseases such as hyperlipidemia. In addition, the PPARα-activating agent, which increases high-density lipoprotein (HDL) cholesterol level and, in blood vessels, suppresses expression of VCAM-1 (a type of cell adhesion factor), is considered to be useful for preventing and/or treating diseases such as arteriosclerosis, and for preventing and/or treating diseases such as diabetes, inflammatory diseases, and heart diseases (Non-Patent Documents 5 and 7 to 14).
Activation of PPARγ in humans has been reported to cause adverse effects of increasing the amount of fat and body weight and causing obesity (Non-Patent Document 13). Recent studies have also reported that a PPARγ antagonist possibly improves insulin resistance (Non-Patent Documents 14 to 16). A document reports that activation of PPARδ causes lipid accumulation (Non-Patent Document 17). Therefore, a PPARα-selective activator exhibiting low PPARγ and PPARδ activities are considered to be a promising agent for prevention and/or treatment, without entailing obesity or increase in body weight, of pathological conditions including hyperlipidemia, arteriosclerosis, diabetes, complications of diabetes, inflammation, and heart diseases.
Under such circumstances, the present inventors previously found that compounds represented by formula (A):
(wherein R1 and R2, which may be identical to or different from each other, each represent a hydrogen atom, a methyl group, or an ethyl group; R3a, R3b, R4a, and R4b, which may be identical to or different from one another, each represent a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, a C1-4 alkyl group, a trifluoromethyl group, a C1-4 alkoxy group, a di-C1-4 alkylamino group, a C1-4 alkylsulfonyloxy group, a C1-4 alkylsulfonyl group, a C1-4 alkylsulfinyl group, or a C1-4 alkylthio group, wherein R3a and R3b may be linked to each other to form an alkylenedioxy group, or R4a and R4b may be linked to each other to form an alkylenedioxy group; D represents an oxygen atom, a sulfur atom, or N—R5 (wherein R5 represents a hydrogen atom, a C1-4 alkyl group, a C1-4 alkylsulfonyl group, or a C1-4 alkyloxycarbonyl group); E represents an oxygen atom, an S(O)t group (wherein t is an integer of 0 to 2), a carbonyl group, a carbonylamino group, an aminocarbonyl group, a sulfonylamino group, or an aminosulfonyl group; G represents CH or N; p is an integer of 1 to 6; and q is an integer of 2 to 6) and salts thereof selectively activate PPARα, and therefore are useful for the prevention and/or treatment, without entailing obesity or increase in body weight, of pathological conditions including hyperlipidemia, arteriosclerosis, diabetes, complications of diabetes, inflammation, and heart diseases, and filed a patent application (Patent Document 1).
The phenyl ether moiety of the compound represented by formula (A) may be produced through phenyl-etherification of a corresponding phenol form as shown below. Patent Document 1 discloses the following applicable procedures: 1) phenyl-etherification in which a phenol form is reacted with a 2-halocarboxylic acid ester in the presence of a base (reaction steps A-1, B-2, C-3, D-1, and E-3); 2) phenyl-etherification in which the OH group of a 2-hydroxycarboxylic acid ester is transformed (e.g., mesylate or tosylate) to a leaving group such as a methanesulfonyloxy group or a p-toluenesulfonyloxy group, and the product is reacted with a phenol form in the presence of a base (reaction steps F-4 and J-4); and 3) Mitsunobu reaction employing a phenol form and a 2-hydroxycarboxylic acid ester.

In the above formula, R1 and R2 have the same meanings as defined above; and R6 represents a group such as C1-4 alkyl.    Patent Document 1: WO 05/23777 pamphlet    Non-Patent Document 1: Nature, 347, 645-650, 1990    Non-Patent Document 2: Cell, 68, pp. 879-887, 1992    Non-Patent Document 3: Cell, 97, pp. 161-163, 1999    Non-Patent Document 4: Biochim. Biophys. Acta., 1302, pp. 93-109, 1996    Non-Patent Document 5: Journal of Medicinal Chemistry, 43, pp. 527-550, 2000    Non-Patent Document 6: Journal of the National Cancer Institute, 90, 1702-1709, 1998    Non-Patent Document 7: Current Opinion in Lipidology, 10, pp. 245-257, 1999    Non-Patent Document 8: Journal of Atherosclerosis and Thrombosis, 3, pp. 81-89, 1996    Non-Patent Document 9: Current Pharmaceutical Design, 3, pp. 1-14, 1997    Non-Patent Document 10: Current Opinion in Lipidology, 10, pp. 151-159, 1999    Non-Patent Document 11: The Lancet, 354, pp. 141-148, 1999    Non-Patent Document 12: Journal of Cardiovascular Risk, 8, pp. 195-201, 2001    Non-Patent Document 13: The Lancet, 349, pp. 952, 1997    Non-Patent Document 14: Proc. Natl. Acad. Sci., 96, pp. 6102-6106, 1999    Non-Patent Document 15: The Journal of Biological Chemistry, 275, pp. 1873-1877, 2000    Non-Patent Document 16: J. Clin. Invest., 108, 1001-1013,    Non-Patent Document 17: Proc. Natl. Acad. Sci., 99, pp. 303-308, 2002